Phosphodiesterase 5 inhibition-induced coronary vasodilation is reduced after myocardial infarction

The balance between the production and removal of cGMP in coronary vascular smooth muscle is of critical importance in determining coronary vasomotor tone and thus in the regulation of coronary blood flow. cGMP production by soluble guanylyl cyclase is activated by nitric oxide (NO), whereas cGMP breakdown occurs through phosphodiesterase 5 (PDE5). We hypothesized that myocardial infarction (MI) alters the balance between the production and removal of cGMP in the coronary vasculature and thereby alters the control of coronary vasomotor tone. Chronically instrumented swine with and without a 2-wk-old MI were exercised on a treadmill in the absence and presence of the PDE5 inhibitor EMD-360527 (300 μg·kg−1·min−1 iv). Inhibition of PDE5 produced coronary resistance vessel dilation, which was more pronounced at rest than during exercise in normal swine. PDE5 gene expression was markedly reduced in coronary resistance vessels isolated from the remote myocardium of MI swine, which was accompanied by a similarly marked attenuation of coronary vasodilation by PDE5 inhibition in MI swine. The coronary vasoconstriction produced by inhibition of NO synthesis with Nω-nitro-l-arginine (20 mg/kg iv) was only slightly smaller in swine with MI. Interestingly, inhibition of NO synthesis reduced the vasodilator response to subsequent PDE5 inhibition in normal swine but not in MI swine. Conversely, PDE5 inhibition enhanced the coronary vasoconstriction produced by NO synthesis inhibition in normal swine but not in MI swine, suggesting that downregulation of PDE5 mitigated the loss of NO vasodilator influence. In conclusion, the expression and vasoconstrictor influence of PDE5 are markedly attenuated in coronary resistance vessels in the remote myocardium after MI, which appears to serve as a compensatory mechanism to mitigate the loss of NO vasodilator influence.

Melatonin potentiates contractile responses to serotonin in isolated porcine coronary arteries

The present study was designed to determine the effects of melatonin on coronary vasomotor tone. Porcine coronary arteries were suspended in organ chambers for isometric tension recording. Melatonin (10−10-10−5 M) itself caused neither contraction nor relaxation of the tissues. Serotonin (10−9-10−5 M) caused concentration-dependent contractions of coronary arteries, and in the presence of melatonin (10−7 M) the maximal response to serotonin was increased in rings with but not without endothelium. In contrast, melatonin had no effect on contractions produced by the thromboxane A2 analog U-46619 (10−10-10−7 M). The melatonin-receptor antagonist S-20928 (10−6 M) abolished the potentiating effect of melatonin on serotonin-induced contractions in endothelium-intact coronary arteries, as did treatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10−5 M), methylene blue (10−5 M), or NG -nitro-l-arginine (3 × 10−5 M). In tissues contracted with U-46619, serotonin caused endothelium-dependent relaxations that were inhibited by melatonin (10−7 M). Melatonin also inhibited coronary artery relaxation induced by sodium nitroprusside (10−9-10−5 M) but not by isoproterenol (10−9-10−5 M). These results support the hypothesis that melatonin, by inhibiting the action of nitric oxide on coronary vascular smooth muscle, selectively potentiates the vasoconstrictor response to serotonin in coronary arteries with endothelium.